Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells (Manning G. et al, (2002) Science, 298: 1912-1934). These enzymes are responsible for transfer of the terminal (gamma) phosphate from ATP to specific amino acid residues of target proteins. Phosphorylation of specific amino acid residues in target proteins can modulate their activity leading to profound changes in cellular signaling and metabolism. Protein kinases can be found in the cell membrane, cytosol and organelles such as the nucleus and are responsible for mediating multiple cellular functions including metabolism, cellular growth and differentiation, cellular signaling, modulation of immune responses, or cell death. Serine kinases specifically phosphorylate serine, or threonine residues in target proteins. Similarly, tyrosine kinases, including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins. Tyrosine kinase families include: Tec, Src, Abl, Jak, Csk, Fak, Syk, Fer, and Ack, and the receptor tyrosine kinase subfamilies including EGFR, FGFR, VEGFR, RET and Eph.
Kinases exert control on key biological processes related to health and disease. Furthermore, aberrant activation or excessive expression of various protein kinases are implicated in the mechanism of multiple diseases and disorders characterized by benign and malignant proliferation, as well as diseases resulting from inappropriate activation of the immune system (Kyttaris V. C., Drug Des. Devel. Ther., 2012, 6:245-50 and Fabbro D. et al. Methods Mol. Biol., 2012, 795:1-34). Thus, inhibitors of select kinases or kinase families are expected to be useful in the treatment of cancer, vascular disease, autoimmune diseases, and inflammatory conditions including, but not limited to: solid tumors, hematological malignancies, thrombus, arthritis, graft versus host disease, lupus erythematosus, psoriasis, colitis, illeitis, multiple sclerosis, uveitis, coronary artery vasculopathy, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergy, dermatomyositis, pemphigus, and the like.
Tec kinases are a family of non-receptor tyrosine kinases predominantly, but not exclusively, expressed in cells of hematopoietic origin (Bradshaw J. M. Cell Signal. 2010,22:1175-84). The Tec family includes Tec, Bruton's tyrosine kinase (Btk), inducible T-cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and bone marrow-expressed kinase (Bmx/Etk). Btk is important in B-cell receptor signaling and regulation of B-cell development and activation (W. N. Khan et al. Immunity, 1995, 3:283-299 and Satterthwaite A. B. et al. Immunol. Rev. 2000,175: 120-127). Mutation of the gene encoding BTK in humans leads to X-linked agammaglobulinemia which is characterized by reduced immune function, including impaired maturation of B cells, decreased levels of immunoglobulin and peripheral B cells, diminished T-cell independent immune response (Rosen F. S. et al., N. Engl. J. Med.,1995, 333:431-440; and Lindvall J. M. et al. Immunol. Rev. 2005, 203:200-215). Btk is activated by Src-family kinases and phosphorylates PLC gamma leading to effects on B-cell function and survival. Additionally, Btk is important in signal transduction in response to immune complex recognition by macrophage, mast cells and neutrophils. Btk inhibition is also important in survival of lymphoma cells (Herman SEM. Blood, 2011, 117:6287-6289) suggesting that inhibition of Btk may be useful in the treatment of lymphomas. As such, inhibitors of Btk and related kinases are of great interest as anti-inflammatory as well as anti-cancer agents. Btk is also important for platelet function and thrombus formation suggesting that Btk-selective inhibitors may prove to be useful antithrombotic agents (Liu J. Blood, 2006,108:2596-603).
Bmx, another Tec family member which has roles in inflammation, cardiovascular disease, and cancer (Cenni B. et al. Int. Rev. Immunol., 2012, 31: 166-173) is also important for self-renewal and tumerogenic potential of glioblastoma stem cells (Guryanova O. A. et al. Cancer Cell 2011,19:498-511). As such, Bmx inhibitors are expected to be useful in the treatment of various diseases including cancer, cardiovascular disease and inflammation.
The SRC family of tyrosine kinases includes cSRC, Lyn, Fyn, Lck, Hck, Fgr, Blk, Syk, Yrk and Yes. cSRC is critically involved in signaling pathways involved in cancer and is often over-expressed in human malignancies (Kim L. C. et al. (2009) Nat. Rev. Clin. Oncol. 6:587-9). cSRC is involved in signaling downstream of growth factor receptor tyrosine kinases and regulates cell cycle progression suggesting that cSRC inhibition would impact cancer cell proliferation. Furthermore, Src inhibitors or downregulation of Hck sensitize tumor cells to immunotoxins (Lui X. F., Mol. Cancer Ther., 2013, Oct. 21).
Inhibition of SRC family members may be useful in treatments designed to modulate immune function. SRC family members, including Lck, regulate T-cell receptor signal transduction which leads to gene regulation events resulting in cytokine release, survival and proliferation. Thus, inhibitors of Lck may be useful immunosuppressive agents with potential application in graft rejection and T-cell mediated autoimmune disease (Martin et al. Expert Opin. Ther. Pat., 2010, 20:1573-93). The Src family member HCK is implicated in regulation of cytokine production suggesting that inhibition of this kinase may be useful in treatment of inflammatory disease (Smolinska M. J. et al. J. Immunol., 2011, 187:6043-51). Additionally, the Src family kinase Fgr is critical for activation of mast cells and IgE-mediated anaphylaxis suggesting that this kinase is a potential therapeutic target for allergic diseases (Lee J. H. et al. J. Immunol., 2011;187:1807-15).
Inhibition of kinases using small molecule inhibitors has successfully led to several approved therapeutic agents used in the treatment of a variety of diseases disorders and conditions. Herein, we disclose a novel family of kinase inhibitors. Further, we demonstrate that modifications in compound substitution can influence kinase selectivity and therefore the biological function of that agent.